A listing of human cancers for which chemotherapy has exerted a redominant role in increasing life span, approaching normal life expectancy, includes Burkitt""s lymphoma, acute lymphocytic leukemia and Hodgkin""s disease, along with about 10-15 other tumor types. For example, see A. Golden et al., Eur. J. Cancer, 17, 129 (1981) (Table 1). While the cure rate of these cancers illustrates the level of success of screening systems in selecting antitumor agents that are effective in man, these responsive tumors represent only a small fraction of the various types of cancer and, notably, there are relatively few drugs highly active against solid tumors such as ovarian cancer, breast cancer, lung cancer and the like. Such drugs include cyclophosphamide, adriamycin, 5-FU, hexamethylmelamine and the like. Thus, patients with many types of malignancies remain at significant risk for relapse and mortality.
After relapse, some patients can be reinduced into remission with their initial treatment regimen. However, higher doses of the initial chemotherapeutic agent or the use of additional agents are frequently required, indicating the development of at least partial drug resistance. Recent evidence indicates drug resistance can develop simultaneously to several agents, including ones to which the patient was not exposed. The development of multiple-drug resistant (mdr) tumors may be a function of tumor mass and constitutes a major cause of treatment failure. To overcome this drug resistance, high-dose chemotherapy with or without radiation and allogenic or autologous bone marrow transplantation can be employed. The high-dose chemotherapy may employ the original drug(s) or be altered to include additional agents. The development of new drugs, non-cross resistant with mdr phenotypes, is required to further the curative potential of current regimens and to facilitate curative interventions in previously treated patients.
The in vitro anti-tumor activity of a novel class of natural products called illudins has been examined by Kelner, M. et al., Cancer Res., 47, 3186 (1987). Illudin M was purified and submitted for evaluation to the National Cancer Institute Division of Cancer Treatment (NCI DCT) in vivo drug screening program. Illudin M significantly increased the life span of rats with Dunning leukemia, but had a low therapeutic index in solid tumor systems. The extreme toxicity of illudins has prevented any applications in human tumor therapy. Recently, synthetic analogs of the illudins have been developed which exhibit promising antitumor activity, including those analogs disclosed in U.S. Pat. Nos. 5,439,936 and 5,523,490.
However, despite these developments, there exists a continuing need for chemotherapeutic agents which inhibit tumor growth, especially solid tumor growth, and which have an adequate therapeutic index to be effective for in vivo treatment.
The invention provides a compound of formula I: 
wherein
R1 is hydrogen, hydroxy, mercapto, amino, halo, carboxy, nitro, or xe2x80x94(CH2)nxe2x80x94(X)xe2x80x94(Y);
n is 0 to 4;
X is oxy (xe2x80x94Oxe2x80x94), thio (xe2x80x94Sxe2x80x94), xe2x80x94N(Ra)xe2x80x94, or absent;
Y is (C3-C6)cycloalkyl, aryl, heteroaryl, a saccharide, an amino acid, a peptide, or a 1 to 15 membered branched or unbranched carbon chain optionally comprising 1, 2, or 3 non-peroxide oxy, thio, or xe2x80x94N(Ra)xe2x80x94; wherein said chain may optionally be substituted on carbon with 1, 2, or 3, oxo (xe2x95x90O), hydroxy, carboxy, halo, mercapto, nitro, xe2x80x94N(Rb)(Rc), (C3-C6)cycloalkyl, aryl, heteroaryl, saccharides, amino acids, or peptides; and wherein said chain may optionally be saturated or unsaturated;
R2 is carboxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, halo(C1-C6)alkyl, xe2x80x94C(xe2x95x90O)NRdRc, a saccharide, an amino acid, a peptide, or (C1-C6)alkyl substituted by 1 or 2 hydroxy, (C1-C6)alkoxy, (C1-C6)alkanoyloxy, carboxy, amino acids, peptides, saccharides, or xe2x80x94C(xe2x95x90O)NRdRe;
R3 is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, aryl, heteroaryl, aryloxy, or heteroaryloxy;
R4 is hydrogen or (C1-C6)alkyl; and R5 is hydroxy, (C1-C6)alkoxy, or (C1-C6)alkanoyloxy; or R4 and R5 taken together are ethylenedioxy;
R6 is hydrogen, carboxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, halo(C1-C6)alkyl, xe2x80x94C(xe2x95x90O)NRfRg, a saccharide, an amino acid, a peptide, or (C1-C6)alkyl optionally substituted by 1 or 2 hydroxy, (C1-C6)alkoxy, (C1-C6)alkanoyloxy, carboxy, amino acids, peptides, saccharides, or xe2x80x94C(xe2x95x90O)NRfRg;
Ra is hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl or benzyl; and
Rb, Rc, Rd, Re, Rf and Rg are each independently hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl or benzyl; or Rb and Rc, Rd and Re, or Rf and Rg, together with the nitrogen to which they are attached, are pyrrolidino, piperidino, or morpholino;
wherein any aryl, heteroaryl, aryloxy, or heteroaryloxy of Y, or R3 may optionally be substituted by 1, 2, or 3 (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-6)alkoxycarbonyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy, halo, carboxy, mercapto, nitro, or xe2x80x94N(Rh)(Rj); wherein each Rh and Rj is independently hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl or benzyl; or Rh and Rj together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino;
or a pharmaceutically acceptable salt thereof.
The invention also provides a compound of formula I wherein: R1 is xe2x80x94(CH2)nxe2x80x94(X)xe2x80x94(Y); n is 0 to 4; X is oxy, thio, xe2x80x94N(Ra)xe2x80x94, or absent; Y is a monoprotected amino acid, a diprotected amino acid, a peptide, or a 1 to 15 membered branched or unbranched carbon chain optionally comprising 1, 2, or 3 non-peroxide oxy, thio, or xe2x80x94N(Ra)xe2x80x94; wherein said chain is substituted with 1, 2, or 3 peptides; and wherein said chain may optionally be saturated or unsaturated; R2 is hydrogen or (C1-C6)alkyl; R3 is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, aryl, heteroaryl, aryloxy, or heteroaryloxy; R4 is hydrogen or (C1-C6)alkyl; and R5 is hydroxy, (C1-C6)alkoxy, or (C1-C6)alkanoyloxy; or R4 and R5 taken together are ethylenedioxy; R6 is hydrogen, carboxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, halo(C1-C6)alkyl, xe2x80x94C(xe2x95x90O)NRfRg, a saccharide, an amino acid, a peptide, or (C1-C6)alkyl optionally substituted by 1 or 2 hydroxy, (C1-C6)alkoxy, (C1-C6)alkanoyloxy, carboxy, amino acids, peptides, saccharides, or xe2x80x94C(xe2x95x90O)NRfRg; Ra is hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl or benzyl; and Rb, Rc, Rd, Re, Rf and Rg are each independently hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl or benzyl; or Rb and Rc, Rd and Re, or Rf and Rg, together with the nitrogen to which they are attached, are pyrrolidino, piperidino, or morpholino; wherein any aryl, heteroaryl, aryloxy, or heteroaryloxy of Y, or R3 may optionally be substituted by 1, 2, or 3 (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy, halo, carboxy, mercapto, nitro, or xe2x80x94N(Rh)(Rj); wherein each Rh and Rj is independently hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl or benzyl; or Rh and Rj together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino; or a pharmaceutically acceptable salt thereof Preferably, Y is (C1-C6)alkyl substituted with a peptide.
The invention also provides a compound of formula I wherein:
R1 is hydrogen, hydroxy, mercapto, amino, halo, carboxy, nitro, or xe2x80x94(CH2)nxe2x80x94(X)xe2x80x94(Y); n is 0 to 4; X is oxy, thio, xe2x80x94N(Ra)xe2x80x94, or absent; Y is (C3-C6)cycloalkyl, aryl, heteroaryl, a saccharide, an amino acid, a peptide, or a 1 to 15 membered branched or unbranched carbon chain optionally comprising 1, 2, or 3 non-peroxide oxy, thio, or xe2x80x94N(Ra)xe2x80x94; wherein said chain may optionally be substituted on carbon with 1, 2, or 3, oxo, hydroxy, carboxy, halo, mercapto, nitro, xe2x80x94N(Ra)(Rc), (C3-C6)cycloalkyl, aryl, heteroaryl, saccharides, amino acids, or peptides; and wherein said chain may optionally be saturated or unsaturated; R2 is hydrogen or (C1-C6)alkyl; R3 is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, aryl, heteroaryl, aryloxy, or heteroaryloxy; R4 is hydrogen or (C1-C6)alkyl; and R5 is hydroxy, (C1-C6)alkoxy, or (C1-C6)alkanoyloxy; or R4 and R5 taken together are ethylenedioxy; R6 is carboxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, xe2x80x94C(xe2x95x90O)NRfRg, a saccharide, an amino acid, a peptide, or (C1-C6)alkyl substituted by 1 or 2 (C1-C6)alkoxy, (C1-C6)alkanoyloxy, carboxy, amino acids, peptides, saccharides, or xe2x80x94C(xe2x95x90O)NRfRg; Ra is hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl or benzyl; and Rb, Rc, Rd, Rc, Rf and Rg are each independently hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl or benzyl; or Rb and Rc, Rd and Re, or Rf and Rg, together with the nitrogen to which they are attached, are pyrrolidino, piperidino, or morpholino; wherein any aryl, heteroaryl, aryloxy, or heteroaryloxy of Y, or R3 may optionally be substituted by 1, 2, or 3 (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy, halo, carboxy, mercapto, nitro, or xe2x80x94N(Rh)(Rj); wherein each Rh and Rj is independently hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl or benzyl; or Rh and Rj together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino; or a pharmaceutically acceptable salt thereof.
The invention also provides dimeric compounds comprising two compounds of formula (I), connected by a linker. The linker can be, for example, an alkyl or ester based linker group. Examples of suitable linkers include xe2x80x94(CH2)pxe2x80x94Oxe2x80x94(CH2)qxe2x80x94, xe2x80x94(CH2)rxe2x80x94, and xe2x80x94CH2xe2x80x94Sxe2x80x94CH2C(O)xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94C(O)CH2xe2x80x94Sxe2x80x94CH2xe2x80x94; wherein p and q are each individually an integer from 1 to 8, inclusive; and r is an integer from 1 to 16, inclusive. Preferably, r is an integer from 1 to 8, inclusive. As would be apparent to one skilled in the art, other linkers of approximately the same length can also be used. Two compounds of formula I can conveniently be linked, for example, by replacing R1, R3, R4 or R5, independently, on each compound of formula I, with the bifunctional linker. When the linkage is through R1, the linker is preferably xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94Sxe2x80x94CH2C(O)xe2x80x94Oxe2x80x94(CH2)2xe2x80x94Oxe2x80x94C(O)CH2xe2x80x94Sxe2x80x94CH2xe2x80x94.
The invention also provides compounds of formula I wherein R1. is xe2x80x94(CH2)nxe2x80x94(X)xe2x80x94(Y); n is 1 to 4 (preferably n is 1); X is oxy, thio, or xe2x80x94N(Ra)xe2x80x94(preferably X is thio); Y is a 2 to 15 membered branched or unbranched carbon chain optionally comprising 1, 2, or 3 non-peroxide oxy, thio, or xe2x80x94N(Ra)xe2x80x94; wherein said chain is substituted on carbon with 1, 2, or 3, oxo, carboxy, mercapto, xe2x80x94N(Rb)(Rc), (C3-C6)cycloalkyl, aryl, heteroaryl, saccharides, amino acids, or peptides; and wherein said chain may optionally be saturated or unsaturated (preferably Y is a 2 to 6 membered branched or unbranched carbon chain that is substituted on carbon with 1, 2, or 3, oxo, heteroaryl, amino acids, or peptides); R2 is hydrogen or (C1-C6)alkyl; R3 is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, aryl, heteroaryl, aryloxy, or heteroaryloxy; R4 is hydrogen or (C1-C6)alkyl; and R, is hydroxy, (C1-C6)alkoxy, or (C1-C6)alkanoyloxy; or R4 and R5 taken together are ethylenedioxy; R6 is hydrogen, carboxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, halo(C1-C6)alkyl, xe2x80x94C(xe2x95x90O)NRfRg, a saccharide, an amino acid, a peptide, or (C1-C6)alkyl optionally substituted by 1 or 2 hydroxy, (C1-C6)alkoxy, (C1-C6)alkanoyloxy, carboxy, amino acids, peptides, saccharides, or xe2x80x94C(xe2x95x90O)NRfRg; Ra is hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl or benzyl; and Rb, Rc, Rf and Rg are each independently hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl or benzyl; or Rb and Rc, or Rf and Rg, together with the nitrogen to which they are attached, are pyrrolidino, piperidino, or morpholino; wherein any aryl, heteroaryl, aryloxy, or heteroaryloxy of Y, or R3 may optionally be substituted by 1, 2, or 3 (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy, halo, carboxy, mercapto, nitro, or xe2x80x94N(Rh)(Rj); wherein each Rh and Rj is independently hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl or benzyl; or Rh and Rj together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino; or a pharmaceutically acceptable salt thereof.
The invention also provides a compound of formula II: 
wherein
R2 is (C1-C6)alkyl;
R3 is hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylthio, aryl, heteroaryl, aryloxy, or heteroaryloxy;
R4 is hydrogen or (C1-C6)alkyl; and R5 is hydroxy, (C1-C6)alkoxy, or (C1-C6)alkanoyloxy; or R4 and R5 taken together are ethylenedioxy;
R6 is hydrogen, carboxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, halo(C1-C6)alkyl, xe2x80x94C(xe2x95x90O)NRfRg, a saccharide, an amino acid, a peptide, or (C1-C6)alkyl optionally substituted by 1 or 2 hydroxy, (C1-C6)alkoxy, (C1-C6)alkanoyloxy, carboxy, amino acids, peptides, saccharides, or xe2x80x94C(xe2x95x90O)NRfRg;
R7 is carboxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, halo(C1-C6)alkyl, xe2x80x94C(xe2x95x90O)NRdRe, a saccharide, an amino acid, a peptide, or (C1-C6)alkyl substituted by 1 or 2 hydroxy, (C1-C6)alkoxy, (C1-C6)alkanoyloxy, carboxy, amino acids, peptides, saccharides, or xe2x80x94C(xe2x95x90O)NRdRe;
Rd, Re, Rf and Rg are each independently hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl or benzyl; or Rd and Re, or Rf and Rg, together with the nitrogen to which they are attached, are pyrrolidino, piperidino, or morpholino;
wherein any aryl, heteroaryl, aryloxy, or heteroaryloxy of R3 may optionally be substituted by 1, 2, or 3 (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, hydroxy, halo, carboxy, mercapto, nitro, or xe2x80x94N(Rh)(Rj); wherein each Rh and Rj is independently hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl or benzyl; or Rh and Rj together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino;
or a pharmaceutically acceptable salt thereof.
Compounds of the invention are useful as antineoplastic agents, i.e., to inhibit tumor cell growth in vitro or in vivo, in mammalian hosts, such as humans or domestic animals, and are particularly effective against solid tumors and multi-drug resistant tumors. Thus, the invention provides a method comprising inhibiting cancer cells, by contacting said cells, in vitro or in vivo, with an effective amount of a compound of the invention. The invention also provides a therapeutic method comprising treating cancer (i.e., inhibiting tumor cell growth) by administering a compound of the invention to a mammal (e.g. a human) in need of such therapy.
The present compounds may be targeted to a particular tumor by attaching the compound to a reagent which is capable of binding to a tumor-associated antigen. The antigen may be located on a tumor or in the tumor cell area. Suitable reagents include polyclonal and monoclonal antibodies. The compound-reagent complex or conjugate may further comprise a linker (e.g. a linker as described hereinabove) for attaching the compound to the reagent. Accordingly, the invention also provides a compound comprising a compound of formula I or formula II and a reagent (e.g. a polyclonal or monoclonal antibody) which is capable of binding to a tumor-associated antigen.
The present invention also provides a pharmaceutical composition (e.g. a pharmaceutical unit dosage form), comprising one or more compounds of the invention in combination with a pharmaceutically acceptable diluent or carrier.
The invention also provides a compound of the invention (e.g. a compound of formula I or II, a dimer thereof, or a conjugate comprising a compound of formula I or II and a reagent that is capable of binding to a tumor-associated antigen, or a salt thereof) for use in medical therapy (preferably for use in treating cancer, e.g. solid tumors), as well as the use of a compound of the invention for the manufacture of a medicament useful for the treatment of cancer, e.g. solid tumors.
The invention also provides processes and novel intermediates disclosed herein that are useful for preparing compounds of the invention. Some of the compounds of the invention are useful to prepare other compounds of the invention.